Bones support the soft tissue and weight of the human body, and surround internal organs to protect the same from external shocks. The bones are also one of the important parts of the human body that structurally support muscles or organs and store calcium or other essential minerals, such as, phosphorus and magnesium, in the body. Therefore, after the completion of growth, adult bones repeat the formation and resorption procedures of removing old bones and substituting for new bones very dynamically and continuously, until death without stopping, thereby maintaining the balance therebetween. This is called bone remodeling. The turnover of bones by removing old bones and substituting for new bones is essential for the restoration of the bone micro-damage caused by growth and stress and the appropriate maintenance of bone functions.
It has been known that two types of cells are greatly involved in bone remodeling: osteoblasts, which form bones; and osteoclasts, which destroy bones. The osteoblasts form a receptor activator of nuclear factor-κB ligand (RANKL) and a decoy receptor thereof, that is, osteoprotegerin (OPG). When RANKL binds to RANK, which is a receptor on a surface of osteoclast progenitor cells, the osteoclast progenitor cells mature into osteoclasts, resulting in bone resorption. However, the binding between OPG and RANKL blocks a binding between RANKL and RANK, thereby inhibiting the formation of osteoclasts and preventing unnecessary bone resorption. The resorption or destruction of old bones occurs by osteoclasts formed from blood cells (hematopoietic stem cells), and makes pores in the bones to release a small amount of calcium into the blood stream, and the calcium is used to maintain physical functions. Meanwhile, the osteoblasts formed from bone cells fill the pores with collagen and cover the precipitates (hydroxyapatite) of calcium and phosphor hydroxyapatite, thereby forming new solid bones and rebuilding the skeleton. It takes about 100 days until the bone is destroyed to form again into new bones. While 100% of the calcium content in bone is changed within 1 year in an infant, about 10-30% of the skeleton is rebuilt by the bone remodeling in an adult every year. Only if the osteoclastic rate is equal to the osteogenic rate, the bone density can be maintained as before. The imbalance in such important bones may cause many diseases, and particularly, the diseases associated with bone damage due to osteoporosis and bone metastasis of cancer cells are representative.
Osteoporosis is a disorder in which the bone mass is decreased by various causes and the risk of bone fracture is continuously increased due to the degeneration of microstructure in bone tissue. Also, osteoporosis is a condition in which the contents of minerals (e.g., calcium) and substrates of bone have been reduced, and osteoporosis occurs when the osteoclasis becomes superior to the osteogenesis to the imbalance of bone remodeling. The interiors of normal bones have dense structures like a mesh, but in the case of osteoporosis, the interval between the structures becomes wider, the microstructure becomes thinner and weakened, and thus, the bone progresses to a state where it can easily fracture by even a small impact. Osteoporosis causes rapid bone loss (2-3% each year) at the time of the beginning of menopause. Osteoporosis diseases are classified into: postmenopausal osteoporosis where the risk of spine compression and wrist bone fracture is increased; senile osteoporosis where it is developed slowly (0.5-1% a year) in elder men and women aged more than 70 years and induces gradual bone loss of hip and spine bones; and secondary osteoporosis wherein it is developed by diseases (endocrine diseases, gastrointestinal diseases, and malignant tumors), drugs (adrenal cortical hormones, anticancer chemotherapy, thyroid hormones, anticonvulsants, antiplatelets, methotexate, cyclosporine and GnRH), alcohol, smoking or accident, regardless of age.
Bisphosphonate-based therapeutics, such as Fosamax, (generic name: alendronate) and Actonel (generic name: risedronate), are being used for the bone damage caused by the above osteoporosis diseases and the bone metastasis of cancer cells. Most of these bisphosphonate-based preparations weaken the functions of osteoclasts destroying bones and induce the apoptosis thereof, thereby delaying or stopping the loss of bones. However, in patients taking bisphosphonates, these drugs do not have an action of promoting the formation of new bones, and the incidence of chronic necrosis (osteonecrosis), severe atrial fibrillation, neutralization of bones and joints, or musculoskeletal pain has been recently increasing year by year. Therefore, a lot of interest is concentrated on the development of preventive and therapeutic agents for osteoporosis, which promotes the bone formation rather than suppressing the bone resorption.
Throughout the entire specification, many papers and patent documents are referenced and their citations are represented. The disclosure of the cited papers and patent documents are entirely incorporated by reference into the present specification, and the level of the technical field within which the present invention falls and the details of the present invention are explained more clearly.